US11123420B2ActiveUtilityA1
Stable live attenuated recombinant dengue vaccine
Est. expirySep 30, 2035(~9.2 yrs left)· nominal 20-yr term from priority
A61K 39/39A61K 2039/5254A61K 47/42A61K 47/02C12N 7/00A61K 9/19A61K 47/183A61K 47/26C12N 2770/24134A61K 2039/70A61K 47/24C12N 2770/24151A61P 31/14A61P 31/12C12N 2770/24171A61K 9/0019A61K 2039/54A61K 39/12Y02A50/30
72
PatentIndex Score
1
Cited by
8
References
22
Claims
Abstract
The present invention relates to field of live attenuated recombinant tetravalent dengue vaccines and methods of producing stable compositions. Present invention specifically relates to a stable composition and methods of using such a stable composition comprising live attenuated recombinant dengue virus, stabilizer, bulking agent and optionally buffering agents, wherein the live attenuated dengue virus is generated from Δ 30 and or Δ 31 deleted or mutated dengue strains. More specifically, the present invention relates to stabilizers for freeze-dried live attenuated immunogenic and/or vaccine compositions that may comprise, inter alia, dengue virus(es). The invention further relates to stabilized, freeze-dried live attenuated immunogenic and/or vaccine compositions of, dengue virus(es), which may contain these stabilizers. Other aspects of the invention are described in or are evident from the following disclosure, and are within the ambit of the invention.
Claims
exact text as granted — not AI-modifiedWe claim:
1. A vaccine composition comprising
(a) Tetravalent live attenuated recombinant dengue virus candidate comprising (rDEN 1Δ30), (rDEN 2/4Δ30), (rDEN 3Δ30/31) and (rDEN 4Δ30); and
(b) Human serum albumin and/or gelatin or hydrolyzed gelatin and/or collagen or hydrolyzed collagen.
2. The vaccine composition according to claim 1 wherein the dengue strains have a phenotype which is temperature sensitive in Vero cells or the human liver cell line HuH-7.
3. The vaccine composition according to claim 1 further comprises bulking agents and/or buffering agents.
4. The vaccine composition according to claim 3 , wherein the bulking agent is selected from a group comprising of lactose, sucrose, mannitol, or trehalose.
5. The vaccine composition according to claim 3 , wherein the buffering agents are selected from the group comprising of potassium dihydrogen-phosphate, Dipotassium hydrogen phosphate, or monosodium glutamate.
6. The vaccine composition according to claim 1 , further comprises supplemental media.
7. The vaccine composition according to claim 1 wherein the final pH of the composition is about 6-7.
8. The vaccine composition according to claim 1 , wherein the said composition is lyophilized.
9. The vaccine composition according to claim 1 wherein the dengue strains are propagated in VERO cells.
10. The vaccine composition according to claim 3 , wherein each of the dengue viruses are present at a dose of not less than 3.0 log 10 PFU per 0.5 ml.
11. The vaccine composition according to claim 8 , wherein the lyophilized vaccine is reconstituted to obtain a stabilized vaccine.
12. The vaccine composition according to claim 1 , wherein human serum albumin and/or gelatin or hydrolyzed gelatin are present in an amount of 1-30 mgs/0.5 ml and/or collagen or hydrolyzed collagen are present in an amount of 1-30 mgs/0.5 ml.
13. The vaccine composition according to claim 12 , wherein human serum albumin is present in an amount of 10-15 mg/0.5 ml.
14. The vaccine composition according to claim 13 , wherein human serum albumin is present in an amount of 12.5 mg/0.5 ml or 10 mg/0.5 ml.
15. The vaccine composition according to claim 12 , gelatin or hydrolyzed gelatin is present in an amount of 12-25 mg/0.5 ml.
16. The vaccine composition according to claim 15 , gelatin or hydrolyzed gelatin is present in an amount of 22 mg/0.5 ml or 15 mg/0.5 ml.
17. The vaccine composition according to claim 12 , wherein collagen or hydrolyzed collagen is present in an amount of 12-25 mg/0.5 ml.
18. The vaccine composition according to claim 17 , wherein collagen or hydrolyzed collagen is present in an amount of 22 mg/0.5 ml or 15 mg/0.5 ml.
19. The vaccine composition according to claim 1 , wherein the said composition is a stable lyophilized tetravalent vaccine comprising Dengue virus serotype 1 (rDEN 1Δ30), Dengue virus serotype 2 (rDEN2/4Δ30), Dengue virus serotype 3 (rDEN 3Δ30/31) and Dengue virus serotype 4 (rDEN 4Δ30), and human serum albumin and/or gelatin or hydrolyzed gelatin and/or collagen or hydrolyzed collagen.
20. The vaccine composition according to claim 19 , wherein each of the dengue viruses are present at a dose of not less than 3.0 log 10PFU per 0.5 ml.
21. The vaccine composition according to claim 19 , wherein the composition is selected from the group consisting of the compositions in the following Tables:
TABLE 1
Quantity
S. No.
Name of the component
(Per dose of 0.5 ml)
1.
Dengue virus serotype 1 (rDEN 1Δ30)*
NLT 3.0 log 10 PFU 1
2.
Dengue virus serotype 2 (rDEN
NLT 3.0 log 10 PFU 1
2/4Δ30)*
3.
Dengue virus serotype 3 (rDEN
NLT 3.0 log 10 PFU 1
3Δ30/31)*
4.
Dengue virus serotype 4 (rDEN 4Δ30)*
NLT 3.0 log 10 PFU 1
Excipients
Range
1.
Human serum albumin
10 to 15
mg
2.
Lactose monohydrate
25 to 50
mg
3.
Sucrose
3 to 25
mg
4.
Potassium dihydrogen phosphate
~260
μg
(KH 2 PO 4 )
5.
Di-potassium hydrogen phosphate
~630
μg
(K 2 HPO 4 )
6.
Monosodium glutamate
~460
μg
7.
Dulbecco's Modified Eagle's Medium
~500
μg
8.
Water for injection
Q.s. to 0.5
ml
TABLE 2
Quantity
S. No.
Name of the component
(Per dose of 0.5 ml)
1.
Dengue virus serotype 1 (rDEN 1Δ30)*
NLT 3.0 log 10 PFU 1
2.
Dengue virus serotype 2 (rDEN
NLT 3.0 log 10 PFU 1
2/4Δ30)*
3.
Dengue virus serotype 3 (rDEN
NLT 3.0 log 10 PFU 1
3Δ30/31)*
4.
Dengue virus serotype 4 (rDEN 4Δ30)*
NLT 3.0 log 10 PFU 1
Excipients
Range
1.
Gelatin
10 to 30
mg
2.
Mannitol
5 to 25
mg
3.
Trehalose
4 to 16
mg
4.
Sucrose
25 to 60
mg
5.
Potassium dihydrogen phosphate
~260
μg
(KH 2 PO 4 )
6.
Di-potassium hydrogen phosphate
~630
μg
(K 2 HPO 4 )
7.
Monosodium glutamate
~460
μg
8.
Dulbecco's Modified Eagle's Medium
~500
μg
9.
Water for injection
Q.s. to 0.5
ml
TABLE 3
Quantity
S. No.
Name of the component
(Per dose of 0.5 ml)
1.
Dengue virus serotype 1 (rDEN 1Δ30)*
NLT 3.0 log 10 PFU 1
2.
Dengue virus serotype 2 (rDEN 2/4Δ30)*
NLT 3.0 log 10 PFU 1
3.
Dengue virus serotype 3 (rDEN 3Δ30/31)*
NLT 3.0 log 10 PFU 1
4.
Dengue virus serotype 4 (rDEN 4Δ30)*
NLT 3.0 log 10 PFU 1
Excipients
Range
1.
Hydrolyzed Gelatin
22
mg
2.
Mannitol
15
mg
3.
Trehalose
8
mg
4.
Sucrose
37.5
mg
5.
Potassium dihydrogen phosphate (KH 2 PO 4 )
~260
μg
6.
Di-potassium hydrogen phosphate (K 2 HPO 4 )
~630
μg
7.
Monosodium glutamate
~460
μg
8.
Dulbecco's Modified Eagle's Medium
~500
μg
9.
Sterile Water for Injection
Q.s. to 0.5
ml
TABLE 7
Quantity
S. No.
Name of the component
(Per dose of 0.5 ml)
1.
Dengue virus serotype 1 (rDEN 1Δ30)*
NLT 3.0 log 10 PFU 1
2.
Dengue virus serotype 2 (rDEN 2/4Δ30)*
NLT 4.0 log 10 PFU 1
3.
Dengue virus serotype 3 (rDEN 3Δ30/31)*
NLT 3.0 log 10 PFU 1
4.
Dengue virus serotype 4 (rDEN 4Δ30)*
NLT 3.0 log 10 PFU 1
Excipients
Range
1.
Gelatin
22
mg
2.
Mannitol
10
mg
3.
Trehalose
5
mg
4.
Sucrose
55
mg
5.
Potassium dihydrogen phosphate (KH 2 PO 4 )
~260
μg
6.
Di-potassium hydrogen phosphate (K 2 HPO 4 )
~630
μg
7.
Monosodium glutamate
~460
μg
8.
Dulbecco's Modified Eagle's Medium
~750
μg
9.
Sterile Water for Injection
Q.s. to 0.5
ml
TABLE 8
Quantity
S. No.
Name of the component
(Per dose of 0.5 ml)
1.
Dengue virus serotype 1 (rDEN 1Δ30)*
NLT 3.0 log 10 PFU 1
2.
Dengue virus serotype 2 (rDEN 2/4Δ30)*
NLT 4.0 log 10 PFU 1
3.
Dengue virus serotype 3 (rDEN 3Δ30/31)*
NLT 3.0 log 10 PFU 1
4.
Dengue virus serotype 4 (rDEN 4Δ30)*
NLT 3.0 log 10 PFU 1
Excipients
Range
1.
Gelatin
15
mg
2.
Mannitol
12
mg
3.
Trehalose
10
mg
4.
Sucrose
55
mg
5.
Potassium dihydrogen phosphate (KH 2 PO 4 )
~270
μg
6.
Di-potassium hydrogen phosphate (K 2 HPO 4 )
~630
μg
7.
Monosodium glutamate
~480
μg
8.
Leibovitz L-15 Medium
~850
μg
9.
Sterile Water for Injection
Q.s. to 0.5
ml
TABLE 9
Quantity
S. No.
Name of the component
(Per dose of 0.5 ml)
1.
Dengue virus serotype 1 (rDEN 1Δ30)*
NLT 3.0 log 10 PFU 1
2.
Dengue virus serotype 2 (rDEN 2/4Δ30)*
NLT 3.0 log 10 PFU 1
3.
Dengue virus serotype 3 (rDEN 3Δ30/31)*
NLT 3.0 log 10 PFU 1
4.
Dengue virus serotype 4 (rDEN 4Δ30)*
NLT 3.0 log 10 PFU 1
Excipients
Range
1.
Hydrolyzed Gelatin
22
mg
2.
Mannitol
12
mg
3.
Trehalose
10
mg
4.
Sucrose
35
mg
5.
Potassium dihydrogen phosphate (KH 2 PO 4 )
~270
μg
6.
Di-potassium hydrogen phosphate (K 2 HPO 4 )
~630
μg
7.
Monosodium glutamate
~480
μg
8.
Leibovitz L-15 Medium
~850
μg
9.
Sterile Water for Injection
Q.s. to 0.5
ml
TABLE 10
Quantity
S. No.
Name of the component
(Per dose of 0.5 ml)
1.
Dengue virus serotype 1 (rDEN 1Δ30)*
NLT 3.0 log 10 PFU 1
2.
Dengue virus serotype 2 (rDEN 2/4Δ30)*
NLT 3.0 log 10 PFU 1
3.
Dengue virus serotype 3 (rDEN 3Δ30/31)*
NLT 3.0 log 10 PFU 1
4.
Dengue virus serotype 4 (rDEN 4Δ30)*
NLT 3.0 log 10 PFU 1
Excipients
Range
1.
Gelatin
15
mg
2.
Mannitol
12
mg
3.
Trehalose
10
mg
4.
Sucrose
55
mg
5.
Potassium dihydrogen phosphate (KH 2 PO 4 )
~270
μg
6.
Di-potassium hydrogen phosphate (K 2 HPO 4 )
~630
μg
7.
Monosodium glutamate
~480
μg
8.
Leibovitz L-15 Medium
~850
μg
9.
Sterile Water for Injection
Q.s. to 0.5
ml
TABLE 11
Quantity
S. No.
Name of the component
(Per dose of 0.5 ml)
1.
Dengue virus serotype 1 (rDEN 1Δ30)*
NLT 3.0 log 10 PFU 1
2.
Dengue virus serotype 2 (rDEN 2/4Δ30)*
NLT 4.0 log 10 PFU 1
3.
Dengue virus serotype 3 (rDEN 3Δ30/31)*
NLT 3.0 log 10 PFU 1
4.
Dengue virus serotype 4 (rDEN 4Δ30)*
NLT 3.0 log 10 PFU 1
Excipients
Range
1.
Hydrolyzed Gelatin
22
mg
2.
Mannitol
20
mg
3.
Trehalose
10
mg
4.
Sucrose
37.5
mg
5.
Potassium dihydrogen phosphate (KH 2 PO 4 )
~270
μg
6.
Di-potassium hydrogen phosphate (K 2 HPO 4 )
~630
μg
7.
Monosodium glutamate
~480
μg
8.
Leibovitz L-15 Medium
~850
μg
9.
Dulbecco's Modified Eagle's Medium
~500
μg
10.
Sterile Water for Injection
Q.s. to 0.5
ml
TABLE 12
Quantity
S. No.
Name of the component
(Per dose of 0.5 ml)
1.
Dengue virus serotype 1 (rDEN 1Δ30)*
NLT 3.0 log 10 PFU 1
2.
Dengue virus serotype 2 (rDEN 2/4Δ30)*
NLT 3.0 log 10 PFU 1
3.
Dengue virus serotype 3 (rDEN 3Δ30/31)*
NLT 3.0 log 10 PFU 1
4.
Dengue virus serotype 4 (rDEN 4Δ30)*
NLT 3.0 log 10 PFU 1
Excipients
Range
1.
Human Serum Albumin
12.5
mg
2.
Lactose monohydrate
37.5
mg
3.
Sucrose
5
mg
4.
Potassium dihydrogen phosphate (KH 2 PO 4 )
~260
μg
5.
Di-potassium hydrogen phosphate (K 2 HPO 4 )
~630
μg
6.
Monosodium glutamate
~460
μg
7.
Dulbecco's Modified Eagle's Medium
−500
μg
8.
Sterile Water for Injection
Q.s. to 0.5
ml
TABLE 16
Quantity
S. No.
Name of the component
(Per dose of 0.5 ml)
1.
Dengue virus serotype 1 (rDEN 1Δ30)*
NLT 3.0 log 10 PFU 1
2.
Dengue virus serotype 2 (rDEN 2/4Δ30)*
NLT 4.0 log 10 PFU 1
3.
Dengue virus serotype 3 (rDEN 3Δ30/31)*
NLT 3.0 log 10 PFU 1
4.
Dengue virus serotype 4 (rDEN 4Δ30)*
NLT 3.0 log 10 PFU 1
Excipients
Range
1.
Human serum albumin
10
mg
2.
Lactose monohydrate
50
mg
3.
Sucrose
10
mg
4.
Potassium dihydrogen phosphate (KH 2 PO 4 )
~260
μg
5.
Di-potassium hydrogen phosphate (K 2 HPO 4 )
~630
μg
6.
Monosodium glutamate
~460
μg
7.
Dulbecco's Modified Eagle's Medium
~600
μg
8.
Sterile Water for Injection
Q.s. to 0.5
ml
TABLE 17
Quantity
S. No.
Name of the component
(Per dose of 0.5 ml)
1.
Dengue virus serotype 1 (rDEN 1Δ30)*
NLT 3.0 log 10 PFU 1
2.
Dengue virus serotype 2 (rDEN 2/4Δ30)*
NLT 4.0 log 10 PFU 1
3.
Dengue virus serotype 3 (rDEN 3Δ30/31)*
NLT 3.0 log 10 PFU 1
4.
Dengue virus serotype 4 (rDEN 4Δ30)*
NLT 3.0 log 10 PFU 1
Excipients
Range
1.
Human serum albumin
10
mg
2.
Lactose monohydrate
25
mg
3.
Sucrose
6.5
mg
4.
Potassium dihydrogen phosphate (KH 2 PO 4 )
~260
μg
5.
Di-potassium hydrogen phosphate (K 2 HPO 4 )
~630
μg
6.
Monosodium glutamate
~480
μg
7.
Leibovitz L-15 Medium
~900
μg
8.
Sterile Water for Injection
Q.s. to 0.5
ml
TABLE 18
Quantity
S. No.
Name of the component
(Per dose of 0.5 ml)
1.
Dengue virus serotype 1 (rDEN 1Δ30)*
NLT 3.0 log 10 PFU 1
2.
Dengue virus serotype 2 (rDEN 2/4Δ30)*
NLT 3.0 log 10 PFU 1
3.
Dengue virus serotype 3 (rDEN 3Δ30/31)*
NLT 3.0 log 10 PFU 1
4.
Dengue virus serotype 4 (rDEN 4Δ30)*
NLT 3.0 log 10 PFU 1
Excipients
Range
1.
Human serum albumin
14
mg
2.
Lactose
40
mg
3.
Sucrose
25
mg
4.
Potassium dihydrogen phosphate (KH 2 PO 4 )
~280
μg
5.
Di-potassium hydrogen phosphate (K 2 HPO 4 )
~640
μg
6.
Monosodium glutamate
~440
μg
7.
Leibovitz L-15 Medium
~500
μg
8.
Sterile Water for Injection
Q.s. to 0.5
ml
TABLE 19
Quantity
S. No.
Name of the component
(Per dose of 0.5 ml)
1.
Dengue virus serotype 1 (rDEN 1Δ30)*
NLT 3.0 log 10 PFU 1
2.
Dengue virus serotype 2 (rDEN 2/4Δ30)*
NLT 3.0 log 10 PFU 1
3.
Dengue virus serotype 3 (rDEN 3Δ30/31)*
NLT 3.0 log 10 PFU 1
4.
Dengue virus serotype 4 (rDEN 4Δ30)*
NLT 3.0 log 10 PFU 1
Excipients
Range
1.
Hydrolyzed Collagen
22
mg
2.
Mannitol
15
mg
3.
Trehalose
8
mg
4.
Sucrose
37.5
mg
5.
Potassium dihydrogen phosphate (KH 2 PO 4 )
~260
μg
6.
Di-potassium hydrogen phosphate (K 2 HPO 4 )
~630
μg
7.
Monosodium glutamate
~460
μg
8.
Dulbecco's Modified Eagle's Medium
~500
μg
9.
Sterile Water for Injection
Q.s. to 0.5
ml
TABLE 22
Quantity
S. No.
Name of the component
(Per dose of 0.5 ml)
1.
Dengue virus serotype 1 (rDEN 1Δ30)*
NLT 3.0 log 10 PFU 1
2.
Dengue virus serotype 2 (rDEN 2/4Δ30)*
NLT 4.0 log 10 PFU 1
3.
Dengue virus serotype 3 (rDEN 3Δ30/31)*
NLT 3.0 log 10 PFU 1
4.
Dengue virus serotype 4 (rDEN 4Δ30)*
NLT 3.0 log 10 PFU 1
Excipients
Range
1.
Collagen
22
mg
2.
Mannitol
10
mg
3.
Trehalose
5
mg
4.
Sucrose
55
mg
5.
Potassium dihydrogen phosphate (KH 2 PO 4 )
~260
μg
6.
Di-potassium hydrogen phosphate (K 2 HPO 4 )
~630
μg
7.
Monosodium glutamate
~460
μg
8.
Dulbecco's Modified Eagle's Medium
~750
μg
9.
Sterile Water for Injection
Q.s. to 0.5
ml
TABLE 23
Quantity
S. No.
Name of the component
(Per dose of 0.5 ml)
1.
Dengue virus serotype 1 (rDEN 1Δ30)*
NLT 3.0 log 10 PFU 1
2.
Dengue virus serotype 2 (rDEN 2/4Δ30)*
NLT 4.0 log 10 PFU 1
3.
Dengue virus serotype 3 (rDEN 3Δ30/31)*
NLT 3.0 log 10 PFU 1
4.
Dengue virus serotype 4 (rDEN 4Δ30)*
NLT 3.0 log 10 PFU 1
Excipients
Range
1.
Hydrolyzed Collagen
15
mg
2.
Mannitol
12
mg
3.
Trehalose
10
mg
4.
Sucrose
55
mg
5.
Potassium dihydrogen phosphate (KH 2 PO 4 )
~270
μg
6.
Di-potassium hydrogen phosphate (K 2 HPO 4 )
~630
μg
7.
Monosodium glutamate
~480
μg
8.
Leibovitz L-15 Medium
~850
μg
9.
Sterile Water for Injection
Q.s. to 0.5
ml.
22. A vaccine kit comprising a first container containing a stabilized vaccine composition according to claim 19 and a second container containing an aqueous solution for the reconstitution of the vaccine.Cited by (0)
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